Antibiotici ad uso specifico

1. Antibiotici ad uso specifico Mycobacterium tuberculosis Clostridium difficile

2. Resistenze e terapie Nel paziente affetto da tubercolosi è verosimile suddividere i bacilli in tre differenti sottopopolazioni: • microorganismi che si sviluppano attivamente in ambiente extracellulare. • una seconda sottopopolazione intracellulare si riproduce più lentamente della precedente nel contesto della necrosi caseosa. • la terza, anch’esse a lenta crescita, si riproduce in ambiente intracellulare ed è quella presente all’interno dei macrofagi e dei monociti

3. Resistenze e terapie Non tutti i farmaci antitubercolari dimostrano la stessa efficacia nei confronti di queste tre sottopopolazioni, infatti isoniazide, streptomicina ed etambutolo risultano essere particolarmente attivi nei confronti delle popolazioni extracellulari metabolicamente attive; la rifampicina sembrerebbe attiva unicamente nei confronti della porzione di bacilli extracellulari. I micobatteri intracellulari sono invece sensibili alla pirazinamide che sperimentalmente si è dimostrata molto efficace

4. Meccanismo d’azione Isoniazide: inibizione sintesi ac micolici Rifampicina: RNA polimerasi Etambutolo: sintesi arabinofuranosilgalattosio componente della parete micobatterica. Pirazinamide abbassa il pH citoplasmatico e disabilita alcuni sistemi di captazione attiva di nutrienti (quali basi pirimidiniche ed aminoacidi).

5. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis José A Caminero, Giovanni Sotgiu, Alimuddin Zumla, Giovanni Battista Migliori Lancet Infect Dis 2010; 10: 621–29

6. Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis José A Caminero, Giovanni Sotgiu, Alimuddin Zumla, Giovanni Battista Migliori Lancet Infect Dis 2010; 10: 621–29

7. Nanotecnologie Per inviare ai macrofagi I farmaci direttamente Resa >3,5 volte DDS, drug delivery systems

8. MT- Nuovi antibiotici Bedaquiline affects the proton pump for ATP synthase. This mechanism is unlike that of the quinolones, whose target is DNA gyrase (on combination with moxifloxacin)

10. MT- Nuovi antibioticiMoxifloxacin and gatifloxacin The fluoroquinolones moxifloxacin (2) and gatifloxacin (3) were marketed in 1999 for respiratory infections and displayed improved Gram-positive antibacterial activity over those of ciprofloxacin and levofloxacin. It was subsequently discovered that these compounds also had improved anti-TB activity compared with older quinolones. Interestingly, M. tuberculosis has not been found to possess any type IV topoisomerase; therefore, fluoroquinolones likely specifically inhibit the mycobacterial DNAgyrase. This raises the possibility of further optimization of topoisomerase inhibitors with improved inhibition of the mycobacterial gyrase enzyme. Gatifloxacin was reported to be slightly more active against M. tuberculosis clinical isolates than moxifloxacin, with an MIC90 range of 0.007 to 0.12 g/ml reported for gatifloxacin and 0.031 to 0.12 g/ml reported for moxifloxacin. In vivo efficacy was demonstrated in murine infection models, as both quinolones were found to equivalent to isoniazid (INH) after 4 weeks of treatment.

11. MT- Nuovi antibioticiDelamanid (OPC-67683) Delamanida nitro-dihydro-imidazooxazole derivative thatinhibitsmycolicacid synthesis and has shown in vitro and in vivo activity against M. tuberculosis MDR strains . This compound displayed an exceptionally low MIC range of 0.006 to 0.024 g/ml and was also highly active against intracellular M. tuberculosis bacilli. In a phase 2 trial it showed safety and efficacy in the treatment of MDRM. tuberculosis for 56 days, patients received either 100 or 200 mg delamanid BID in addition to an optimized background regimen was found to be associated with an increase in sputum culture. Most adverse events were mild to moderate in severity. Delamanidcould enhance treatment options for MDR strains Under clinical developmente (phase 3)

12. MT- Nuovi antibioticiPA-824. Among the compounds in phase 2 clinical trials for treatment of TB is PA-824, a small-molecule nitroimidazopyran drug candidate Nitroimidazopyransinhibit the synthesis of protein and cell wall lipid nitroimidazopyransitexhibitedbactericidalactivityagainstbothreplicating and staticM. tuberculosis. after activation by a mechanism dependent on M. tuberculosis F420 cofactor. PA-824 was tested in vitro against a broad panel of MDR M. tuberculosis isolates and was found to be highly active against all isolates, with MICs of 1 g/ml. The compound was also found to be efficacious in both short-course and long-term mouse infection models. In a recent early bactericidal activity phase 2 study, a PA-824–moxifloxacin–pyrazinamide regimen was found to be potentially suitable for treating drug-sensitive and MDR TB, and the treatments appeared to be safe and well tolerated.

13. MT- Nuovi antibioticiSQ109. SQ109 is an orally active antibiotic for treatment of pulmonary TB. It is a 1,2-diamine related to ethambutoland possesses a novel mechanism of action by disrupting cell wall assembly by targeting MmpL3, a transporter of mycobacterial trehalosemonomycolate. SQ-109 was initially found to have good MICs (1 M), 99% inhibition activity against intracellular bacteria, in vivo potency, and limited in vitro and in vivo toxicity. In the phase 1 clinical trial program, SQ109 was studied at doses of up to 300 mg and exhibited a good safety profile with a 60-h half-life. It is hoped that SQ109 could become a component in first-line TB drug regimens, potentially simplifying therapy and shortening currentTB treatment regimens.

14. MT- Nuovi antibioticiLinezolid The oxazolidinone antibiotic linezolid has been found to have efficacy against M. tuberculosis and is under investigation in phase 2 clinical trials for use in therapeutic regimens including treatment of patients with extensively drug-resistant (XDR) M. tuberculosis. Effectiveness at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis was observed, but numerous patients reported adverse events, including anemia, thrombocytopenia, and/or peripheral and optic neuropathy. These results, although promising, suggest a cautious approach for both dosage and length of treatment for linezolid in M. tuberculosis infections. These promising microbiological and clinical data have inspired additional research on the oxazolidinone class of antibiotics to find compounds with an improved safety profile.

15. MT- Nuovi antibioticiSutezolid Oneneweroxazolidinone, sutezolid (PNU-40080) is a sulfur-containing linezolid analog with an active sulfoxide metabolite. The mean MIC was found to be 3.2 times lower than that for linezolid for M. tuberculosis clinical isolates with various susceptibilities to isoniazid (INH), rifampin, ethambutol, and streptomycin. PNU-100480 also demonstrated improved efficacy in murine models of tuberculosis, and earlier sterilization (1 to 2 months) was observed when it was combined with standard TB drugs. In phase 1 clinical studies, doses of up to 600 mg BID were generally safe and reasonably well tolerated for up to 28 days, and no significant safety signals were observed. Sutezolid is currently in phase 2 clinical development and has recently completed a study in newly diagnosed, treatment-sensitive patients with pulmonary TB to assess early bactericidal and whole-blood activities

16. MT- Nuovi antibioticiPosizolid Posizolid(AZD5847, AZD2563) was originally in development as a once-daily i.v./oral treatment for staphylococcal infections as an improvement over twice-daily linezolid dosing. However, development was discontinued in 2002 when pharmacokinetics in healthy volunteers did not support once-daily i.v. dosing. The compound was later repositioned for the treatment of tuberculosis by oral administration. Posizolid demonstrated activity against extracellular, intracellular, rapidly dividing, and slowly dividing M. tuberculosis in mouse models of tuberculosis, and pharmacokinetics were consistent with once-daily dosing for TB. It was generally safe and well tolerated over 14 days in healthy volunteers, although reversible changes in white blood cell (WBC) and reticulocyte counts were observed at the highest exposures tested. AZD5847 is in phase 2 clinical studies to assess the early bacterial activity (EBA) over 14 days at four different doses and in subjects with newly diagnosed sputum smear-positive pulmonary TB. There is potential for AZD5847 to distinguish itself among TB drugs due to activity against slowly dividing bacteria, activity against intracellular bacilli, and reduced inhibition of human mitochondrial proteinsynthesis.

17. MT- Nuovi antibioticiSQ609 SQ609 an adamantine- containing hydroxydipiperidine, was identified after screening a 10,240-compound library based on commercially available amino acids and containing a dipiperidinepharmacophore. It displayed promising anti-M. tuberculosis activity, including against MDR isolates, with a mechanism that targets the mycobacterial cell wall. SQ609 demonstrated good activity against M. tuberculosis strains, inhibiting more than 90% of intracellular bacterial growth at 4 g/ml without toxicity. In addition, in vivo efficacy was demonstrated in a mouse infection model, where it completely prevented TB induced weight loss and improved survival compared to results for mice treated with moxifloxacin or ethambutol. Therapeutic effects continued for 2 weeks after cessation of treatment. SQ609 has several attributes that support further clinical development, including activity against intracellular M. tuberculosis, high specificity for M. tuberculosis, good aqueous solubility, oral bioavailability, and a favorable in vitro safety pharmacology. It also showed additive or synergistic activity with first-line TB drugs, suggesting that it could added to or replace one of the drugs in the current first-line regimen

18. MT- Nuovi antibioticiPerchlosone Studies dealing with the design of new antituberculous agents based on goal-oriented synthesis have provided the agent Perchlosone which is similar to isoniazid and rifampicin, produces in tuberculostatic activity against sensitive laboratory cultured mycobacteria, produces an inhibitory action on polyresistant clinical strains. Experiments on animals (mice, rabbits) with experimental tuberculosis have established that Perchlosone and isoniazid have equal therapeutical properties, and the former shows a synergist interaction with rifampicin, has neither mutagenic activity nor negative effects on immunity and the surfactant system of the lung.

19. MT- Nuovi antibioticiDiphenyl urea Mycobacterium tuberculosis inosine monophosphate dehydrogenase (IMPDH) as a novel drug target was explored . IMPDH exclusively catalyzes the conversion of inosine monophosphate (IMP) to xanthosine monophosphate (XMP) in the presence of the cofactor nicotinamide adenine dinucleotide (NAD+). Although the enzyme is a dehydrogenase, the enzyme does not catalyze the reverse reaction i.e. the conversion of XMP to IMP. Unlike other bacteria, M. tuberculosis harbors three IMPDH-like genes, designated as Mt-guaB1, Mt-guaB2 and Mt-guaB3 respectively. Of the three putative IMPDH’s, we previously confirmed that Mt-GuaB2 was the only functional ortholog by characterizing the enzyme kinetically. Using an in silico approach based on designed scaffolds, a series of novel classes of inhibitors was identified. The inhibitors possess good activity against M. tuberculosis with MIC values in the range of 0.4 to 11.4 mg mL21 . Among the identified ligands, two inhibitors have nanomolar Ki s against the Mt-GuaB2 enzyme.

20. CD- Nuovi antibioticiFidaxomicin Fidaxomicin is a macrolide-like antibiotic that is structurally similar to lipiarmycin and inhibits the initiation of bacterial RNA synthesis that is not orally absorbed. Its mechanism of action is distinct from that of elongation inhibitors and transcription imitation inhibitors such as the rifamycins. It is highly active against C. difficile (MIC90, 0.25 μg/ml) including the epidemic strain but with poor activity against both aerobic Gram-negative and most anaerobic fecal flora isolates. This has been shown to clinically preserve the human fecal flora during and after CDI therapy and reduces both toxin expression and CDI recurrence. OP-1118 is its major metabolite, but has an MIC90 of 8 μg/ml. Fidaxomicin was well tolerated in clinical trials

21. CD- Nuovi antibioticiAmixicile Amixicile is derivative of nitizoxanide which is a synthetic nitrothiazole benzamide agent with poor solubility and acts by interfering with anaerobic metabolic pathways. It has been shown to have excellent in vitro activity against C. difficile with an MIC90 of 0.125 μg/ml. Clinical studies indicated that nitazoxanide was found to be non inferior to vancomycin. Sustained response rates were 78% (18 of 23 patients) for the vancomycin group, and 89% (16 of 18 patients) for the nitazoxanide group. However, the study had a small sample size. In patients who failed metronidazole therapy, nitazoxanide yielded 66% (aggregate cure rate). Nitaxozanide shows a potential role in patients who fail metronidazole therapy. Nitazoxanide shows limited potential in the initial treatment of recurrent CDI.

22. CD- Nuovi antibioticiSurotomycin Surotomycin (CB-315, CB-183,315), is an investigational lipopeptide oral antibiotic for the treatment of C. difficile infections. It is structurally related to daptomycin and appears to share its mechanism of action. When tested against S. aureus, surotomycin dissipated the membrane potential of target cells without inducing changes in membrane permeability to small molecules, and it is assumed to do the same against C. difficile. When assayed against more than 200 C. difficile clinical isolates, this antibiotic exceeded the potency of vancomycin by 4-fold and that of metronidazole by greater than 16-fold, and all isolates were inhibited at concentrations of 1 g/ml. The drug is bactericidal and stays at the site of infection in the intestinal tract with minimal systemic absorption or disruption of normal bowel flora. In phase 2 trials, surotomycin demonstrated strong cure rates comparable to those for vancomycin and significantly reduced rates of recurrence compared to those with vancomycin (17% compared to 36%, respectively). The drug was generally safe and well tolerated. Two phase 3 clinical trials evaluating the safety and efficacy of surotomycin compared with vancomycin are ongoing.

23. CD- Nuovi antibioticiCadazolid Cadazolid (ACT-179811) is a quinolonyl-oxazolidinone chimeric antibiotic with structural elements of an oxazolidinone and a quinolone. A phase 2 dose-finding study evaluated the efficacy, safety, and tolerability of three doses of cadazolid (administered orally, twice daily) versus vancomycin (125 mg administered orally, four times daily) for 10 days. The results of this study indicated that the effects of all doses were equivalent or superior to those of vancomycin on key endpoints, including cure rates and sustained cure rates. In addition, recurrence rates were lower for all doses of cadazolid than for vancomycin. The drug was safe and well tolerated, with no safety signals identified to date.

24. CD- Nuovi antibioticiLFF571 LFF571. Synthesized and tested 4-aminothiazolyl analogs of the antibiotic natural product GE2270A for activity against C. difficile infection. A series of dicarboxylic acid derivatives with solubility and efficacy that were improved by several orders of magnitude compared to those of earlier compounds were discovered, and this led to the selection of LFF571, a semisynthetic thiopeptide that is an inhibitor of bacterial translation acting via inhibition of elongation factor Tu . This compound possesses potent activity against C. difficile and most other Gram-positive anaerobes, displaying MIC90 values of 0.25 g/ml, with the exception of bifidobacteria and lactobacilli . In preliminary clinical studies the drug was found to be safe and well tolerated and had limited systemic exposure and high steady-state fecal concentrations. A phase 2 clinical trial is currently in progress to assess safety and efficacy of multiple daily dosing of oral LFF571 in patients with moderate C. difficile infections.

25. CD- Nuovi antibioticiNVB302 NVB302 is a novel type B lantibiotic under evaluation for the treatment of C. difficile infections. This compound is not absorbed well, resulting in optimal concentration in the gastrointestinal tract at the site of infection, enhancing efficacy and lessening resistance selection. It is highly selective for C. difficile versus normal gut flora, which may diminish the chance for recurrent infections. NVB302 displayed non inferiority to vancomycin in the treatment of simulated C. difficile infection in an in vitro human gut model. In a phase 1 clinical trial in healthy volunteers, and NVB302 was found to be safe and well tolerated, with negligible systemic absorption of the drug and high concentrations recovered in the feces.